Synthesis and biological evaluation of rare monosaccharides and their mimics

• Main Author: Liu, Zilei
• Other Authors: Fleet, George ; Wormald, Mark
• Published: University of Oxford 2016
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.728773

This thesis describes work in the synthesis and biological evaluation of different carbohydrates and their derivatives. Azetidine carboxylic acid (Aze), as a pharmacophore in medicinal chemistry, is attracting more and more researchers in recent years. As a four membered ring analogue of proline, this nature occurring compound can be mis-incorporated into proteins and can cause changes in protein conformation and therefore induce toxic effects. It is therefore useful to study how Aze and its derivatives affect protein confirmation. Previous research has identified some azetidine iminosugars to be promising inhibitors of certain glycosidases. Chapter 2 describes the synthesis, from D-glucose, of various novel 3-fluoro-Aze, 3-azido-Aze analogues and a trans,trans-3,4-difluoro-proline as novel peptidomimetics. Short oligomers of these amino acids were synthesized. A number of 3-fluoro-azetidine iminosugars were obtained to test their inhibition of glycosidases and cancer cell growth. A 3-fluoro-azetidine diol showed significant growth inhibition of several different human cancer cell lines compared with anti-cancer drugs 5-fluorouracil and gemcitabine. Most rare sugars are still difficult to produce in quantity by either chemical or biotechnological methods. Some of them have interesting activities and potential applications; however, research on these rare sugars is constrained by their high price and inaccessibility. In Chapter 3 an approach to economically and easily produce rare sugars, in high purity, is developed. A number of rare sugars, including L-glucose, D-gulose, D-idose and 6-deoxy-hexoses, were synthesized from cheap D-glucose or its derivatives on large scales and in high yields. Complicated purification methods were avoided. The development of this methodology can contribute not only to the accessibility of these expensive sugars but also to increase their availability for biological evaluation. The L-rhamnose inducible promoter system (L-rhamnose operon) in E. coli. is a commercially available gene expression system which is widely used for various purposes. L-Rhamnose regulates the gene expression of L-rhamnose operon in E. coli. Moreover, L-rhamnose processing enzymes play crucial roles in different pathogenic bacteria while they have no role in mammalian metabolism, suggesting L-rhamnose processing enzymes could be potential therapeutic targets. Searching for L-rhamnose analogues, which have induction activity for the L-rhamnose operon, or specific inhibitory activity towards L-rhamnose processing enzymes, is of both commercial and academic interest. In Chapter 4 the synthesis of a large number of L-rhamnose analogues, including 6-deoxy-hexoses and 6-deoxy-iminosugars, from L-rhamnose, is described. Biological assays identified five hexoses as non-metabolizable inducers for the L-rhamnose operon and several inhibitors of L-rhamnosidases and rhamnose isomerases.